scholarly journals Cholangiocarcinoma with respect to IgG4 Reaction

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Kenichi Harada ◽  
Yasuni Nakanuma
Keyword(s):  
T Cells ◽  
Plasma Cells ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Intraepithelial Neoplasia ◽  
Cell Switching ◽  
Igg4 Related Disease ◽  
Regulatory Cytokine ◽  
High Risk Factor ◽  
Antigen Presenting

IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

scholarly journals Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment

2020 ◽  
Vol 3 (3) ◽  
pp. 179-192
Author(s):  
Sukhbir Kaur ◽  
Kyle V Cicalese ◽  
Rajdeep Banerjee ◽  
David D Roberts
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cytotoxic T Cells ◽  
Regulatory Protein ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Clinical Development ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Thrombospondin 1

ABSTRACT CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-α (SIRPα). Engaging SIRPα on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRPα signaling in antigen-presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies and development of antibodies that recognize tumor-specific epitopes of CD47, SIRPα antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of antibodies and related biologics that inhibit CD47/SIRPα signaling are reviewed, including strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers.

Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease

2019 ◽  
Vol 32 (3) ◽  
pp. 163-174
Author(s):  
Takanori Sasaki ◽  
Taiki Yajima ◽  
Tatsuro Shimaoka ◽  
Shuhei Ogawa ◽  
Takashi Saito ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effect ◽  
Plasma Cells ◽  
Synergistic Effects ◽  
Lymphoid Tissues ◽  
Irreversible Damage ◽  
Tissue Specific ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Igg4 Antibody

Abstract IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.

scholarly journals IgG4‐related disease: Association with a rare gene variant expressed in cytotoxic T cells

2019 ◽  
Vol 7 (6) ◽  
Author(s):  
John H. Newman ◽  
Aaron Shaver ◽  
Jonathan H. Sheehan ◽  
Simon Mallal ◽  
John H. Stone ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Disease Association ◽  
Gene Variant ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Rare Gene

Rag1 Deficiency Does Not Affect Myelodysplasia but Leads to More Rapid Leukemic Transformation in a Mouse Model of MDS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2784-2784
Author(s):  
Sheryl M Gough ◽  
Yang Jo Chung ◽  
Peter D. Aplan
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Peripheral Blood ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Severe Anemia ◽  
Control Groups ◽  
Leukemic Transformation ◽  
Significant Difference

Abstract Abstract 2784 Poster Board II-760 MDS comprises a premalignant heterogeneous group of clonal stem cell disorders that also show bone marrow dysplasia and which often evolve to acute myeloid leukemia (AML). Aplastic anemia (AA) patients also share the bone marrow failure, anemia and resulting peripheral blood cytopenias of MDS. AA is thought to be caused by an oligoclonal expansion of cytotoxic T-cells that target haematopoietic stem and progenitor cells. The severe anemia and leucopenia characteristic of both diseases is relieved in AA patients and some MDS patients by immunosuppressive therapy, supporting the role of cytotoxic T-cells in the etiology of AA. However, the role of the lymphocytes in progressive MDS remains unclear. MDS has been associated with a number of genetic aberrations, including chromosomal translocations involving the NUP98 gene. Using mice that express a NUP98-HOXD13 (NHD13) transgene, previously shown to manifest the same clinical symptoms as those of MDS patients, we have followed a cohort of NHD13/Rag1−/− mice to determine if the absence of lymphocytes, especially T cells, might 1) diminish the severity of the MDS, or 2) effect transformation and/or survival in the NHD13 mice, as would be predicted by an “immune surveillance” hypothesis of malignant transformation. Serial CBCs at two month time intervals were used to evaluate the extent of anemia and leucopenia in NHD13+ /Rag1+/+ and NHD13/Rag1−/−, as well as WT/Rag1+/− and WT/Rag1−/− control groups over a 15 month period. NHD13/Rag1−/− mice were generated by crossing the NHD13+ (C57BL/6) with the B6;129S7-Rag1tm1Mom/J mouse, and housed in a Specific Pathogen-Free (SPF) environment. Mice were euthanized and analyzed when CBCs indicated severe anemia/leucopenia or leukemic transformation, or when determined to be unwell (hunched, immobile, dyspnea) by observation. Flow cytometry, histology and genomic analyses further determined leukemia subtype, extent of infiltration and leukemia clonality. NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice showed no significant differences at any two month time-point in hemoglobin (Hg), mean corpuscular volume (MCV), or platelet levels, and progressive MDS occurred in both groups. Consistent with previous studies, and excluding cases that showed evident transformation to acute leukemia, NHD13+ /Rag1+/+ mice showed low WBC, neutrophil and lymphocyte numbers, which were not significantly different from the NHD13/Rag1−/− mice. NHD13/Rag1−/− mice did however show a significantly reduced survival when compared with the NHD13+ /Rag1+/+ mice (Log-rank test, p = 0.0135), and survival medians of 11 and 13 months, respectively. Incidence of leukemic transformation was increased in the NHD13/Rag1−/− compared with the NHD13+ /Rag1+/+ mice (p=0.0079). A range of leukemia subtypes was observed in both the NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice, including myeloid, B-cell, T-cell, and erythroid leukemias. In the SPF environment provided, the WT/Rag1+/− and WT/Rag1−/− control groups showed no significant difference in survival rates. Serial CBC data indicated that there was no significant difference in the timing or degree of peripheral blood cytopenias between the NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice, supporting the conclusion that absence of lymphocytes does not lead to improvement in the peripheral blood cytopenias caused by the NHD13 transgene. This observation suggests that the NHD13 transgene does not produce MDS caused by an autoimmune phenomenon. The poorer survival and increased frequency of leukemic transformation in the NHD13/Rag1−/− mice suggests that lymphocytes might play a role in the evolution of MDS to AML in the NHD13 mouse model, and supports the ‘immune surveillance' hypothesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cytotoxic CD4 T Cells in Antiviral Immunity

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Nikki B. Marshall ◽  
Susan L. Swain
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Antiviral Immunity ◽  
Effective Vaccine ◽  
Antigenic Determinants ◽  
The Many ◽  
And Function

CD4 T cells that acquire cytotoxic phenotype and function have been repeatedly identified in humans, mice, and other species in response to many diverse pathogens. Since CD4 cytotoxic T cells are able to recognize antigenic determinants unique from those recognized by the parallel CD8 cytotoxic T cells, they can potentially contribute additional immune surveillance and direct effector function by lysing infected or malignant cells. Here, we briefly review much of what is known about the generation of cytotoxic CD4 T cells and describe our current understanding of their role in antiviral immunity. Furthering our understanding of the many roles of CD4 T cells during an anti-viral response is important for developing effective vaccine strategies that promote long-lasting protective immunity.

Phospholipase C-like protein 2 (PLC-L2) is associated with cytolytic ability of CD8+ T cells and prognosis of prostate cancer

2020 ◽  
Vol 10 (5) ◽  
pp. 725-732
Author(s):  
Kaiwen Li ◽  
Xiaoming Ma ◽  
Qiong Wang ◽  
Qianghua Zhou ◽  
Xu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Clinical Stage ◽  
The Cancer Genome Atlas ◽  
Tnf Alpha ◽  
Epigenetic Marker ◽  
Cancer Genome Atlas ◽  
Positive Correlations ◽  
Antigen Presenting ◽  
The Relationship

PLC-L2, whose related members of its family facilitate in the differentiation of T cells, is a potential epigenetic marker for PCa. The density of tumor-infiltrating CD8+ T cells in PCa is associated with a better prognosis. It remains unclear how PLC-L2 affects the TIL and PCa. A human tissue microarray (TMA) and PCa patients from the Cancer Genome Atlas were used to address the correlations between PLC-L2 and the infiltrated immune cells and to evaluate the relationship between PLC-L2 and prognosis of PCa patients. More advanced PCa expressed less PLC-L2 than less advanced PCa, in terms of pathological grade, clinical stage, and the presence of lymph node and distant metastasis. Besides, the expression of PLC-L2 had positive correlations with CD8+ T cells and antigen-presenting cells such as macrophage and dendritic cells. PLC-L2 expression was also positively correlated with local immune cytolytic ability, TNF-alpha, IFN-gamma, IL-12A, IL-12B, and IL-18. Furthermore, PLC-L2 expression was an independent factor of a favorable prognosis in PCa patients. This study reveals that PLC-L2 might recruit CD8+ T cells and promote their cytolytic ability in PCa. PLC-L2 accompanied by CD8+ cytotoxic T cells could suppress the development of PCa and subsequently increase prognosis in PCa patients.

scholarly journals Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8+ Cytotoxic T Cells

2007 ◽  
Vol 81 (12) ◽  
pp. 6584-6593 ◽  
Author(s):  
Meghann Teague Getts ◽  
Byung S. Kim ◽  
Stephen D. Miller
Keyword(s):  
T Cells ◽  
Demyelinating Disease ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Disease Model ◽  
Tolerance Induction ◽  
Virus Clearance ◽  
Fatal Reaction ◽  
Virus Epitope ◽  
Antigen Presenting

ABSTRACT Tolerance induced by the intravenous injection of peptide-pulsed, ethylene carbodiimide (ECDI)-fixed splenic antigen-presenting cells (Ag-SP) is a safe and effective method of inducing specific unresponsiveness in CD4+ T cells for the prevention and treatment of a variety of autoimmune diseases. We determined whether Ag-SP tolerance could also be used to tolerize CD8+ T cells. We show in the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease model of multiple sclerosis that CD8+ T cells specific for both dominant and subdominant epitopes can be rendered tolerant. Interestingly, although virus clearance was delayed, lack of the virus-specific cytotoxic T-lymphocyte response did not result in the conversion of normally TMEV-resistant C57BL/6 mice to a susceptible phenotype. Importantly, we found that Ag-SP tolerance may not be a practical treatment for human diseases in which CD8+ T cells play a major role in pathogenesis, as tolerance induction in mice previously infected with TMEV led to a severe, often fatal reaction.

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